Karthik V. Giridhar

Disseminated herpes zoster in chronic lymphocytic leukemia (CLL) patients treated with B-cell receptor pathway inhibitors

Ibrutinib and idelalisib are new targeted therapies that are changing the landscape of treating chronic lymphocytic leukemia (CLL). With an increased use of these agents, a rise in opportunistic infections, including pneumocystis jiroveci,[1] cytomegalovirus (CMV) reactivation, and hepatitis-B reactivation,[2] have emerged as previously unrecognized toxicities. We present three cases of patients with CLL on targeted therapy who presented with disseminated varicella zoster infection, two of whom had visceral disease involving the pancreas. Case 1: A 66-year-old female with relapsed CLL presented in December 2015, two weeks after starting idelalisib with abdominal pain. She was previously treated with pentostatin, cyclophosphamide, and rituximab (PCR; 2013), ibrutinib (2014), bendamustine and rituximab (2015), and pembrolizumab (on clinical trial, 2015). She reported constant periumbilical pain with radiation to her back and associated nausea/vomiting. Her temperature was 36.2 C, heart rate of 81 beats/minute, respiratory rate of 27 breaths/minute, and blood pressure of 166/ 89mmHg. On examination, she had mild epigastric tenderness. A contrast computed tomography (CT) scan of her abdomen and pelvis showed decreased size of her mesenteric adenopathy when compared to 5 weeks prior to starting idelalisib. The initial labs showed no elevation in liver enzymes or lipase (Table 1). On the third day of hospitalization (HD3), her abdominal pain acutely worsened. Repeat CT scan with contrast showed no radiographic abnormalities (Figure 1(A)). Due to her persistent pain, she underwent upper endoscopy, which discovered white esophageal plaques (Figure 1(C)) and multiple tiny duodenal erosions. The laboratories showed new elevation of lipase and transaminases (Table 1). A third CT scan (HD6) revealed a new moderate peripancreatic fluid collection and new onset peripancreatic lymphadenopathy consistent with acute pancreatitis (Figure 1(B)). Late that evening, she developed a single vesicular lesion on her back, which progressed into a diffuse vesicular rash over her torso and back the following day (Figure 1(D)). These lesions were swabbed and biopsied and she was empirically started on 10mg/kg/dose of intravenous acyclovir. The skin lesions returned positive for varicella zoster virus (VZV) DNA by polymerase chain reaction (PCR). The esophageal biopsies also returned positive for VZV by immunohistochemistry. She later developed oral ulcerations that were also positive for VZV by PCR. Despite IV acyclovir, she developed confusion and tachypnea, necessitating transfer to the ICU followed by intubation and mechanical ventilation for six days. Her rash improved, the oral ulcerations resolved, and she was transitioned to a rehabilitation facility after a 36-day hospitalization. She received IV acyclovir for 6 weeks with the intention to transition to lifelong suppressive valacyclovir. Each time she was converted from IV acyclovir to 1000mg oral valacyclovir twice daily, she had recurrence of her zoster, requiring multiple subsequent hospitalizations. Idelalisib was never restarted. Due her to ongoing physical decline and poor quality of life, she elected to transition to hospice and passed away. Case 2: A 77-year-old male with relapsed CLL and associated Evans syndrome initiated ibrutinib for relapsed disease (July 2015). The only prior therapy that he had received for CLL was PCR (2008). Eleven months after initiating ibrutinib, he presented for evaluation after several days of epigastric pain. His temperature was 37.1 C, heart rate of 91 beats/minute, and blood pressure 178/ 87mmHg. On examination, he had moderate epigastric tenderness. The initial laboratories showed elevation of lipase and transaminases (Table 1). A CT scan showed decreased abdominal lymphadenopathy along with mild increased density in peripancreatic fat. On HD3, he underwent an upper endoscopy and a 1 cm mucosal abnormality in the posterior wall of the stomach was identified and biopsied. Due to worsening abdominal pain, a magnetic resonance cholangiopancreatography (MRCP) was performed and showed

Plasma exosomal miRNAs-based prognosis in metastatic kidney cancer

Plasma exosomal miRNAs were evaluated for prognosis in an initial set of 44 metastatic renal cell cancer (mRCC) patients by RNA sequencing. Among ~3.49 million mappable reads per patient, miRNAs accounted for 93.1% of the mapped RNAs. 227 miRNAs with high abundance were selected for survival analysis. Cox regression analysis identified association of 6 miRNAs with overall survival (OS) (P<0.01, False discovery rate (FDR) < 0.3). Five of the associated miRNAs were quantified in an independent follow-up cohort of 65 mRCC patients by TaqMan-based miRNA assays. Kaplan-Meier analysis confirmed the significant OS association of three miRs; miR-let-7i-5p (P=0.018, HR=0.49, 95% CI=0.21-0.84), miR-26a-1-3p (P=0.025, HR=0.43, 95% CI=0.10-0.84) and miR-615-3p (P=0.0007, HR=0.36, 95% CI=0.11-0.54). A multivariate analysis of miR-let-7i-5p with the clinical factor-based Memorial Sloan-Kettering Cancer Center (MSKCC) score improved survival prediction from an area under the curve (AUC) of 0.58 for MSKCC score to an average AUC of 0.64 across 48-month follow-up time. The multivariate model was able to define a high-risk group with median survival of 14 months and low risk group of 39 months (P=0.0002, HR=3.43, 95%CI, 2.73-24.15). Further validation of miRNA-based prognostic biomarkers are needed to improve current clinic-pathologic based prognostic models in patients with mRCC.Plasma exosomal miRNAs were evaluated for prognosis in an initial set of 44 metastatic renal cell cancer (mRCC) patients by RNA sequencing. Among ∼3.49 million mappable reads per patient, miRNAs accounted for 93.1% of the mapped RNAs. 227 miRNAs with high abundance were selected for survival analysis. Cox regression analysis identified association of 6 miRNAs with overall survival (OS) (P<0.01, False discovery rate (FDR) < 0.3). Five of the associated miRNAs were quantified in an independent follow-up cohort of 65 mRCC patients by TaqMan-based miRNA assays. Kaplan-Meier analysis confirmed the significant OS association of three miRs; miR-let-7i-5p (P=0.018, HR=0.49, 95% CI=0.21-0.84), miR-26a-1-3p (P=0.025, HR=0.43, 95% CI=0.10-0.84) and miR-615-3p (P=0.0007, HR=0.36, 95% CI=0.11-0.54). A multivariate analysis of miR-let-7i-5p with the clinical factor-based Memorial Sloan-Kettering Cancer Center (MSKCC) score improved survival prediction from an area under the curve (AUC) of 0.58 for MSKCC score to an average AUC of 0.64 across 48-month follow-up time. The multivariate model was able to define a high-risk group with median survival of 14 months and low risk group of 39 months (P=0.0002, HR=3.43, 95%CI, 2.73-24.15). Further validation of miRNA-based prognostic biomarkers are needed to improve current clinic-pathologic based prognostic models in patients with mRCC.

Whole Blood mRNA Expression-Based Prognosis of Metastatic Renal Cell Carcinoma

The Memorial Sloan Kettering Cancer Center (MSKCC) prognostic score is based on clinical parameters. We analyzed whole blood mRNA expression in metastatic clear cell renal cell carcinoma (mCCRCC) patients and compared it to the MSKCC score for predicting overall survival. In a discovery set of 19 patients with mRCC, we performed whole transcriptome RNA sequencing and selected eighteen candidate genes for further evaluation based on associations with overall survival and statistical significance. In an independent validation of set of 47 patients with mCCRCC, transcript expression of the 18 candidate genes were quantified using a customized NanoString probeset. Cox regression multivariate analysis confirmed that two of the candidate genes were significantly associated with overall survival. Higher expression of BAG1 [hazard ratio (HR) of 0.14, p < 0.0001, 95% confidence interval (CI) 0.04–0.36] and NOP56 (HR 0.13, p < 0.0001, 95% CI 0.05–0.34) were associated with better prognosis. A prognostic model incorporating expression of BAG1 and NOP56 into the MSKCC score improved prognostication significantly over a model using the MSKCC prognostic score only (p < 0.0001). Prognostic value of using whole blood mRNA gene profiling in mCCRCC is feasible and should be prospectively confirmed in larger studies.

Serum chromogranin-A-based prognosis in metastatic castration-resistant prostate cancer

Objective:To determine the prognostic value of serum chromogranin-A (CGA) in a two-cohort study of men with metastatic castrate resistant prostate cancer (mCRPC) and to compare with circulating tumor cells (CTCs)-based prognosis.Patients and methods:A two-cohort-based evaluation for serum CGA for prognostication in CRPC stage was performed using a screening cohort of 256 men with mCRPC and an independent validation cohort of 92 men with mCRPC. In both cohorts, men receiving proton pump inhibitors and those with non-castrate levels of testosterone (>50 ng/dl) were excluded. Serum CGA was measured in a homogeneous automated immunofluorescent assay using time-resolved amplified cryptate emission. In the validation cohort, CTC enumeration was also performed using the FDA-cleared CELLSEARCH® CTC test. Cox proportional hazard regression models were used for prognostic association of serum CGA and CTC counts with overall survival.Results:In the screening cohort, 200 men were eligible for analysis. The median serum CGA was 100.3 ng/mL (interquartile range: 67–161.3) and 34/200 were above the reference range. In the subset of men with Gleason scores ≥ 8, elevated CGA was associated with shorter overall survival [hazard ratio (HR) 2.19, p = 0.017]. In the validation cohort for 71 men eligible for analysis, the median serum CGA was 90 ng/mL (interquartile range: 55–156) and 31/71 patients had an elevated CGA. 51% of patients had a Gleason score ≥ 8 and 66/71 patients had CTCs enumerated with 26/66 with a CTC count ≥ 5 per 7.5 ml blood sample (unfavorable). Both elevated serum CGA (HR: 1.91, p = 0.043) and unfavorable CTC counts (HR: 2.97, p = 0.0012) were adversely associated with overall survival and patients with ≥ 5 CTCs and elevated serum CGA had the shortest overall survival (HR: 3.76, p = 0.008).Conclusion:Elevated serum CGA was negatively associated with OS in men with mCRPC. Serum CGA represents a prognostic biomarker that may complement CTC enumeration.

Management of Muscle-Invasive Urothelial Cancer and the Emerging Role of Immunotherapy in Advanced Urothelial Cancer

Abstract The incidence of bladder cancer has increased in the past decade, and mortality from bladder cancer remains a substantial public health burden. After 3 decades of minimal progress in the treatment of advanced‐stage disease, recent advances in the genomic characterization of urothelial cancer and breakthroughs in bladder cancer therapeutics have rejuvenated the field. This review highlights the landmark clinical trials of chemotherapy in both the neoadjuvant and advanced or metastatic urothelial carcinoma settings. We describe treatment paradigms for multimodal treatment of locally advanced bladder cancer, including discussion on bladder preservation strategies. Lastly, we discuss novel immunomodulatory, targeted, and combination therapies in development for the treatment of advanced urothelial carcinoma.